Specific inhibition of Wee1 kinase and Rad51 recombinase: A strategy to enhance the sensitivity of leukemic T-cells to ionizing radiation-induced DNA double-strand breaks

Havelek, Radim; Ćmielová, Jana; Královec, Karel; Brůčková, Lenka; Bı́lková, Zuzana; Fousova, Ivana; Šinkorová, Zuzana; Vávrová, Jiřina; Řezáčová, Martina

doi:10.1016/j.bbrc.2014.09.123

Cited by 13 publications

(12 citation statements)

References 13 publications

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“…Coincidentally, a latest study published by Havelek R et al explored the effects of co-targeting Wee1 kinase and Rad51 recombinase using specific small molecular inhibitors on radiation sensitivity in human leukemic T-cells. In conformity with our data, they found that the combination treatment resulted in a further enhancement of radiosensitivity, which was associated with the abrogation of G2 cell cycle arrest and impairment of DNA damage repair [50].…”

Section: Discussionsupporting

confidence: 86%

Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair

Wang¹,

Lai²,

Ma³

et al. 2015

Cancer Letters

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Section: Discussionsupporting

confidence: 86%

Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair

Wang¹,

Lai²,

Ma³

et al. 2015

Cancer Letters

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“…Pre-treatment of the human leukemic T-cell lines, Jurkat and MOLT-4, with the WEE-1 inhibitor 681641 or the Rad51 inhibitor RI-1 increases the sensitivity of Jurkat cells to irradiation. However, combining both inhibitors together results in a further enhancement of apoptosis (Havelek et al, 2014 ).…”

Section: Pharmacological Inhibitor Of Wee-1 Kinasementioning

confidence: 99%

Targeting cell cycle regulators in hematologic malignancies

Aleem

Arceci

2015

Front. Cell Dev. Biol.

108

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Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.

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“…Since the last decades have witnessed tremendous advances in the understanding and treatment of cancers, oncological patients still die due to resistance of cancer cells to therapy. These resistant cells drive grow of tumors and contribute to the dissemination of malignant cells into vital organs (Mellor and Callaghan, 2008;Havelek et al, 2014). Common mechanisms responsible for cancer cells resistance represent the upregulation of DNA damage sensing and repair capacity of cells (Beskow et al, 2009;Ader et al, 2002) induction of cell cycle arrest allowing time for DNA damage repair (Gogineni et al, 2011;Vávrová et al, 2004) and defects in the apoptosis signalling machinery (Snyder and Morgan, 2004).…”

Section: Introductionmentioning

confidence: 97%

“…Because p53 mutants are highly expressed in cancer cells (in over 50% of human cancers) and not in normal cells, target therapy against p53 deficient cells may eliminate these cancer cells by cell death. Therefore, substantial efforts are being invested into identifying and developing compounds that would be able target resistant forms of tumor cells while not damage healthy cells (Havelek et al, 2014;Ghobrial et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic activities of Amaryllidaceae alkaloids against gastrointestinal cancer cells

Doskočil

Hošťálková

Šafratová

et al. 2015

Phytochemistry Letters

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Specific inhibition of Wee1 kinase and Rad51 recombinase: A strategy to enhance the sensitivity of leukemic T-cells to ionizing radiation-induced DNA double-strand breaks

Cited by 13 publications

References 13 publications

Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair

Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair

Targeting cell cycle regulators in hematologic malignancies

Cytotoxic activities of Amaryllidaceae alkaloids against gastrointestinal cancer cells

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